Childhood Absence Epilepsy (CAE) is the most common childhood onset epilepsy syndrome, accounting for 10-17% of all childhood onset epilepsy. In its first 6 years, the 32 center CAE trial successfully completed a double blind randomized controlled comparative trial (NS045911 and NS045803) comparing short term outcomes for ethosuximide, lamotrigine and valproic acid as initial therapy for children with newly diagnosed CAE characterized by only absence seizures. The CAE trial established ethosuximide as the optimal initial short term therapy for children with newly diagnosed CAE. However, it is clear that long term outcomes remain the crucial outcomes that should be used to determine optimal therapy. We propose to use this well characterized, carefully monitored cohort treated through a randomized controlled trial to determine if ethosuximide maintains its superior effectiveness (freedom from failure) over the long term along with better seizure freedom, seizure remission, cognitive and safety outcomes than lamotrigine or valproic acid in this well defined idiopathic epilepsy syndrome. Serial assessment of seizure control (including occurrence of generalized tonic clonic seizures), seizure remission, behavioral/emotional status, quality of life and growth will occur over the entire 4 years of the study. All CAE subjects and a cohort of 150 comparable healthy unrelated control subjects will be assessed using a new neuropsychological testing battery to better understand the CAE subjects' neuropsychological function at 6 years after start of therapy. This study's results will identify the optimal initial monotherapy for best long term outcomes. These results will address knowledge gaps about the long term comparative effectiveness of initial monotherapy for CAE and allow clinicians to make more evidence based treatment decisions for initial therapy to optimize both seizure and cognitive long term outcomes. RELEVANCE: Epilepsy (CAE) is the most common childhood epilepsy syndrome. Although a recent clinical trial of 446 children with CAE found ethosuximide as optimal initial short term therapy, is it not clear how short term results relate to long term outcomes. Optimal long term therapy can be determined by following these children for four more years.